rs534961012

Variant names:

• chr2-178528742-C-G
• rs534961012
• NM_001267550.2:c.107009G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178528742-C-G
• chr2-178528742-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.107009G>C​(p.Arg35670Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,252 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R35670K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.52
• Publications: 0 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07302222).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.107009G>C	p.Arg35670Thr	missense	Exon 360 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.102086G>C	p.Arg34029Thr	missense	Exon 310 of 313	NP_001243779.1
	TTN	NM_133378.4		c.99305G>C	p.Arg33102Thr	missense	Exon 309 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.107009G>C	p.Arg35670Thr	missense	Exon 360 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.106853G>C	p.Arg35618Thr	missense	Exon 358 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.106733G>C	p.Arg35578Thr	missense	Exon 358 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000322 AC: 8 AN: 248268 AF XY: 0.0000371

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1460952 Hom.: 1 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726614

African (AFR) AF: 0.000866 AC: 29 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111360

Other (OTH) AF: 0.000215 AC: 13 AN: 60346

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74474

African (AFR) AF: 0.000217 AC: 9 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000413 AC: 5

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.81
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.064
Sift	Benign	0.26	T
Polyphen		0.055	B
Vest4		0.36
MVP		0.21
MPC		0.14
ClinPred		0.078	T
GERP RS		-0.59
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs534961012; hg19: chr2-179393469;